Ebselen analogues delay disease onset and its course in fALS by on-target SOD-1 engagement.


Watanabe, Seiji, Amporndanai, Kangsa, Awais, Raheela, Latham, Caroline, Awais, Muhammad, O'Neill, Paul M ORCID: 0000-0003-4338-0317, Yamanaka, Koji and Hasnain, S Samar (2024) Ebselen analogues delay disease onset and its course in fALS by on-target SOD-1 engagement. Scientific reports, 14 (1). p. 12118. ISSN 2045-2322, 2045-2322

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Abstract

Amyotrophic lateral sclerosis (ALS) selectively affects motor neurons. SOD1 is the first causative gene to be identified for ALS and accounts for at least 20% of the familial (fALS) and up to 4% of sporadic (sALS) cases globally with some geographical variability. The destabilisation of the SOD1 dimer is a key driving force in fALS and sALS. Protein aggregation resulting from the destabilised SOD1 is arrested by the clinical drug ebselen and its analogues (MR6-8-2 and MR6-26-2) by redeeming the stability of the SOD1 dimer. The in vitro target engagement of these compounds is demonstrated using the bimolecular fluorescence complementation assay with protein-ligand binding directly visualised by co-crystallography in G93A SOD1. MR6-26-2 offers neuroprotection slowing disease onset of SOD1G93A mice by approximately 15 days. It also protected neuromuscular junction from muscle denervation in SOD1G93A mice clearly indicating functional improvement.

Item Type: Article
Uncontrolled Keywords: Amyotrophic lateral sclerosis, Superoxide dismutase, Drug development, Target engagement, Ebselen, Riluzole, Motor neuron disease
Divisions: Faculty of Health & Life Sciences
Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > Inst. Systems, Molec & Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 19 Sep 2024 10:50
Last Modified: 23 May 2026 11:16
DOI: 10.1038/s41598-024-62903-5
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URI: https://livrepository.liverpool.ac.uk/id/eprint/3184607
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